Microbiota transfer therapy for Pitt Hopkins Syndrome

Abstract

Provided herein are compositions and methods for treating Pitt Hopkins Syndrome (PTHS) by restoring PTHS patient's gut microbiota. These methods can be used with PTHS patient with or without ongoing gastrointestinal symptoms. The methods comprise administering a therapeutic composition comprising a fecal microbe or a fecal microbe preparation to the subject.

What is claimed is: 
     
       1. A method for treating Pitt Hopkins syndrome (PTHS) in a subject in need thereof, comprising
 administering to the subject a fecal microbe preparation comprising at least 1×10 9  cells for at least 12 weeks, thereby reducing severity of PTHS symptoms in the subject by at least 10% as determined by a clinical global impression scale applied to the subject before and after the treatment. 
 
     
     
       2. The method of  claim 1 ,
 wherein the clinical global impression scale is selected from Parent Global Impressions of PTHS—Revised (PGI-PTHS), Clinical Global Impression (CGI) tool for PTHS symptoms (CGI-PTHS), revised Face Legs Activity Crying Consolability Pain Questionnaire for Children with Cognitive Impairment (FLACC), and any combination thereof. 
 
     
     
       3. The method of  claim 1 , wherein the subject suffers from gastrointestinal (GI) symptoms selected from abdominal pain, diarrhea, constipation, and any combination thereof. 
     
     
       4. The method of  claim 1 , wherein the fecal microbe preparation comprises:
 (i) a complete community of microbes obtained from a healthy donor; 
 (ii) a full spectrum microbiome from a healthy donor; and/or 
 (iii) a manipulated total fecal microbiome obtained from a healthy donor. 
 
     
     
       5. The method of  claim 1 , wherein the fecal microbe preparation comprises:
 (i) a synthetic preparation of predetermined fecal microbes; 
 (ii) a synthetic fecal composition of predetermined microbes in proportional content that resembles a normal healthy human fecal flora; 
 and/or 
 (iii) a synthetic preparation comprising a diversity of gut bacteria comprising at least  Prevotella , or commensal Clostridia species. 
 
     
     
       6. The method of  claim 1 , further comprising pretreating the subject before administering the fecal microbe preparation. 
     
     
       7. The method of  claim 6 , wherein the pretreating the subject comprises one or more of: (a) treating the subject with an antibiotic; (b) cleansing the bowel of the subject; and (c) fasting the subject for one or more days. 
     
     
       8. The method of  claim 7 , wherein (a) the antibiotic is a non-absorbable antibiotic; and/or (b) cleansing the bowel of the subject comprises ingestion of magnesium citrate, polyethylene glycol or a combination thereof. 
     
     
       9. The method of  claim 6 , wherein the pretreating the subject comprises:
 (a) administering to the subject vancomycin for 10 days; 
 (b) fasting the subject for up to one day; 
 (c) cleansing the bowel of the subject by ingestion of magnesium citrate; or 
 (d) a combination thereof. 
 
     
     
       10. The method of  claim 1 , wherein the fecal microbe preparation is administered to the subject in one or more high doses; and/or in one or more low doses;
 wherein the one or more high doses each comprises more than 10 11  cells but fewer than 10 12  cells in the fecal microbe preparation; and 
 wherein the one or more low doses each comprises more than 10 9  cells but fewer than 10 11  cells in the fecal microbe preparation. 
 
     
     
       11. The method of  claim 10 , wherein
 (a) the one or more high doses of the fecal microbe preparation each comprises more than 10 11  cells but fewer than 9×10 11  cells and is administered daily or two times a day; and/or 
 (b) the one or more high doses are administered for 4 days. 
 
     
     
       12. The method of  claim 10 , wherein administering the one or more high doses of the fecal microbe preparation is followed by administering the one or more low doses of the fecal microbe preparation. 
     
     
       13. The method of  claim 12 , wherein
 (a) the one or more low doses of the fecal microbe preparation each comprises more than 5×10 9  cells but fewer than 10 11  cells; and/or 
 (b) the one or more low doses of the fecal microbe preparation are administered every four days for at least 12 weeks. 
 
     
     
       14. The method of  claim 1 , wherein the fecal microbe preparation is lyophilized. 
     
     
       15. The method of  claim 1 , wherein the fecal microbe preparation is administered orally, optionally as a solid dosage form selected from the group consisting of capsule, tablet, powder, and granule, or is administered rectally by endoscopy or rectal enema. 
     
     
       16. The method of  claim 15 , wherein the fecal microbe preparation is formulated as an acid-resistant capsule. 
     
     
       17. The method of  claim 1 , wherein:
 (a) the subject exhibits at least a 20% reduction in severity of PTHS symptoms at 2 years after the treatment as compared to the severity of PTHS symptoms before initiating the treatment; 
 (b) the microbiome diversity in the subject is restored to the microbiome diversity level of a neurotypical individual; or 
 (c) the subject exhibits at least a 30% reduction in severity of GI symptoms, optionally, maintained for at least 2 years from the start of the treatment. 
 
     
     
       18. The method of  claim 17 , wherein
 (a) the severity of the PTHS symptoms is measured using one or more scales selected from Parent Global Impressions of PTHS—Revised (PGI-PTHS), clinical global impression (CGI) tool for PTHS symptoms (CGI-PTHS), and revised Face Legs Activity Crying Consolability Pain Questionnaire for Children with Cognitive Impairment (FLACC); 
 (b) the microbiome diversity is assessed using a non-phylogenetic metric, observed operational taxonomic units (OTUs), a phylogenetic distance (PD) index, or any combination thereof; and/or 
 (c) the severity of the GI symptoms is assessed using Daily Stool and Symptom Record, clinical global impression (CGI) tool for GI symptoms (CGI-GI), Gastrointestinal Symptom Rating Scale (GSRS), or any combination thereof. 
 
     
     
       19. A method of normalizing phylogenetic diversity of fecal microbiota in a subject having PTHS and experiencing gastrointestinal (GI) symptoms, comprising
 administering to the subject a fecal microbe preparation comprising at least 1×10 9  cells for at least 12 weeks, thereby reducing severity of the subject's GI symptoms by at least 20% as assessed by Daily Stool and Symptom Record, clinical global impression (CGI) tool for GI symptoms (CGI-GI), Gastrointestinal Symptom Rating Scale (GSRS), or any combination thereof.